The major cause of mortality from prostate cancer is metastatic disease, and the bone is the most common site for metastasis. Reciprocal signaling between cancer cells and host bone cells is key to metastatic tumor development. Understanding these cell-cell interactions will lead to effective diagnostic and therapeutic strategies to prevent/arrest metastatic spread of prostate carcinoma. My studies on Sonic hedgehog (Shh)-Gli signaling led me to independently postulate that this pathway, which is utilized by epithelial and mesenchymal cells in the developing prostate for ductal morphogenesis and by prostate epithelial cancer cells and stroma to promote tumor growth, might also be active during metastasis. I hypothesize that prostate cancer cells and osteoblasts collaborate to promote bone metastasis via the Shh-Gli pathway. As a newly independent investigator, I have been successful in obtaining preliminary data consistent with my hypothesis and which form the basis for this proposal. I now plan to show that Shh-Gli signaling between prostate cancer cells and osteoblasts regulates cell functions crucial to bone metastasis, to determine the role of this pathway in the formation and growth of prostate tumor with osteoblastic characteristics, and to identify downstream target genes that could be potential effectors of bone metastasis. I expect the proposed research to generate data and new ideas and concepts that I will develop into an independent research program to further investigate signaling mechanisms that uniquely promote prostate cancer metastasis to bone. Now is an opportune time for me to establish an independent cancer research program. I have had invaluable research insights and training in excellent signaling and prostate cancer labs, I have initiated collaboration with other scientists, and I have the full commitment and support of my institution to advance my career as an independent scientist. Support from the Research Career Award will allow me to pursue a career path as an independent researcher committed to understanding prostate cancer metastasis to bone.